The human pancreas secretes over a liter of enzyme and zymogen containing fluid per day as part of its role in the major digestive activity of the gastrointestinal tract. Regulation of pancreatic secretion is by both hormonal and neural mechanisms, with the former being of primary importance. The secreted enzymes include amylases, lipases, and proteolytic enzymes, which may be packaged in precursor form or in combination with inhibitors to prevent autodigestion of pancreatic cells. Enzyme secretion is also regulated in part by a negative feedback mechanism induced by enzyme levels in the duodenum.
Pancreatitis is an inflammatory disease which may be clinically diagnosed as acute or chronic. For a review of the above, see Greenberger N J et al. Chapter 260: Acute and Chronic Pancreatitis. Wilson J D et al. eds. Harrison's Principles of Internal Medicine. 12th Ed. New York: McGraw Hill, 1991:1372-83. See also the web site of by eMedicine.com, Inc., emedicine.com/med/topic1720.htm, and The Merck Manual of Diagnosis and Therapy, section 3, chapter 26, an online version of which can be found on the merck.com website at merck.com/pubs/mmanual/section3/chapter26/26b.htm, for a full description of the pathophysiology, clinical course, and current treatment of acute and chronic pancreatitis.
If pancreatic enzymes and toxins released during acute pancreatitis gain access to the system circulation via retroperitoneal, lymphatic and/or venous pathways, they can affect capillaries and generally cause harmful systemic effects. Respiratory distress syndrome, renal failure and/or heart failure are the most frequent causes of death in patients with acute pancreatitis.
An estimated 50,000 to 80,000 cases of acute pancreatitis occur in the U.S. each year. Most cases in the U.S. are caused either by alcohol abuse or by gallstones. Other causes may be use of prescription drugs, trauma or surgery to the abdomen, or abnormalities of the pancreas or intestine. In rare cases, the disease may result from viral infections, such as mumps. In about 15% of cases, the cause is unknown.
Acute pancreatitis occurs suddenly and may be a severe, life-threatening illness with many complications. Usually, the condition is self-limited and the patient recovers completely. The major symptom is abdominal pain, and conventional treatments include analgesics for pain, intravenous fluids, no oral intake, and nasogastric suction to decrease gastrin release from the stomach.
If injury to the pancreas continues, such as when a subject persists in drinking alcohol, a chronic form of the disease may develop, bringing severe pain and reduced functioning of the pancreas that affects digestion and causes weight loss. Chronic pancreatitis may also result from other causes, many of which are also known to induce acute pancreatitis. Chronic pancreatitis may also develop from undetermined causes. While pain is also often seen in chronic pancreatitis, the pain may be continuous or intermittent or absent.
In contrast to acute or reoccurring acute pancreatitis, serum amylase and lipase levels are not elevated in patients with chronic pancreatitis. Oral administration of conventional pancreatic enzymes have been demonstrated to decrease abdominal pain in patients with chronic pancreatitis. This observation is consistent with the negative feedback regulation hypothesized for pancreatic exocrine secretion.
Generally, therapeutic approaches used to date against pancreatitis aim to minimize further enzyme secretion (limiting further damage and inflammation), treat pain (for which narcotics may be required), maintain circulatory function, prevent secondary infection, and eventually, in chronic cases, correction of malabsorption. Strategies for limiting enzyme secretion include:                1) preventing passage of nutrients from the stomach into the duodenum (such as by nasogastric suction and intravenous alimentation);        2) preventing acid from entering the duodenum (which normally prompts secretin release and results in pancreatic stimulation; it should be noted that cimetidine to limit acid secretion has not been shown useful in treating pancreatitis);        3) blocking enzymatic secretion, as with anticholinergic drugs for example (which has not been shown useful); and        4) inhibiting protease activity, as with aprotinin (Traysylol™) for example (which has been shown ineffective in practice).        
Amylin, a 37 amino acid peptide hormone co-secreted with insulin in response to nutrient stimuli from pancreatic β-cells, inhibits insulin secretion from β-cells and glucagon secretion from α-cells (see Cooper, G. J., et al., Prog. Growth Fact. Res. (1998) 1:99-105, Ogawa et al. J. Clin. Invest. (1990) 85:973-976, Silvestre, R. A., et al., Regul. Pept. (1990) 31:23-31, Young, A. A., et al., Diabetologia (1995) 38:642-648, and Gedulin, B. R., et al., Metabolism (1997) 46(1):67-70). Amylin, at doses resulting in physiological plasma concentrations, regulates nutrient absorption by inhibiting gastric emptying, food intake and, in a rat model of cholecystokinin octapeptide (CCK-8), induces lipase and amylase secretion (see Young et al., Morley et al. Peptides (1991) 12:865-869, Gedulin et al. Diabetes (1998) 47(Suppl 1), abstract 1086). Amylin showed no effect on basal pancreatic enzyme secretion in the rat model. Additionally, it inhibits gastric acid secretion with similar potency (see Gedulin, B., et al., Diabetologia (1997) 40(Suppl 1), abstract 1177).
Amylin has been examined extensively in preclinical and clinical settings (e.g., as a treatment for diabetes), and is well tolerated by animals, including humans.